Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz)

NCT03850964 | Active Not Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: HT2CDMRP-PR2034731R01FD006840-01A1
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 11

Brief Summary

During the Efficacy Study (Part B), the investigators will study whether Pazopanib, taken daily for 24 weeks, will reduce the severity of nose bleeds in patients with hereditary hemorrhagic telangiectasia (HHT). Patients will either be provided active drug or a placebo \[sugar - inactive pill\], and be tested for nose bleed severity throughout the trial, including particularly nose bleed duration. Investigators will also test for blood loss, as well as for safety. This study is funded by the US Department of Defense USAMRAA and FDA/OOPD.

Conditions

Epistaxis; Anemia; Nosebleed; HHT; Hereditary Hemorrhagic Telangiectasia

Keywords

Osler-Weber-Rendu; Hereditary Hemorrhagic Telangiectasia; Patient Reported Outcome; HHT; Anemia; Nosebleed; Epistaxis

Outcome Measures

Primary Outcomes (2)

• Change in epistaxis duration in minutes

  \>=50% decrease in the duration of epistaxis in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)

  Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline.

• Hemoglobin Response rate increase in hemoglobin

  Increase in hemoglobin by ≥ 2 g/dl in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)

  Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline.

Secondary Outcomes (5)

• Achievement of meaningful improvement in epistaxis for HHT patients

  Baseline [screening, run-in and 0 time points] and week 24.

• Percent change in blood transfusion rate in the Severe Cohort

  Baseline, and weeks 13-24

• Assess the safety of up to 24 and 48 weeks of treatment of pazopanib

  1st dose of intervention until Weeks 24 and 48

• Assess pharmacokinetics and pharmacodynamics (PK/PD) of treatment

  Weeks 12, 24, 36 and 48

• Establish comparability of endpoint outcomes for each hemoglobin stratification

  Baseline, Weeks 19-24, Week 48

Other Outcomes (13)

• Assess effects of up to 24 weeks of pazopanib treatment on epistaxis duration

  Baseline and weeks 19-24 of study.

• Assess the effects of up to 24 weeks of pazopanib treatment on hemoglobin levels

  Baseline and weeks 19-24 of study

• Assess the effects of up to 24 weeks of pazopanib treatment on frequency of nose bleeds and speed of flow

  Baseline and weeks 19-24 of study

Study Arms (5)

Part B (Severe Anemia) Pazopanib - 150 mg

ACTIVE COMPARATOR

150 mg pazopanib oral capsules (six 25 mg placebo capsules daily).

Drug: Pazopanib

Part B (Severe Anemia) Placebo

PLACEBO COMPARATOR

Placebo oral capsules (six 25 mg placebo capsules daily).

Drug: Placebo oral capsule

Part B (Severe Epistaxis) Pazopanib - 150 mg

ACTIVE COMPARATOR

Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).

Drug: Pazopanib

Part B (Severe Epistaxis) Placebo

PLACEBO COMPARATOR

Placebo oral capsules (six 25 mg placebo capsules daily).

Drug: Placebo oral capsule

Part C Pazopanib - 150 mg

EXPERIMENTAL

Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).

Drug: Pazopanib

Interventions

Pazopanib DRUG

gel capsule, with 25mg-similar fills

Also known as: Votrient

Part B (Severe Anemia) Pazopanib - 150 mg; Part B (Severe Epistaxis) Pazopanib - 150 mg; Part C Pazopanib - 150 mg

Placebo oral capsule DRUG

identical gel capsule without active pharmaceutical ingredient

Also known as: cellulose capsule

Part B (Severe Anemia) Placebo; Part B (Severe Epistaxis) Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A definite or probable diagnosis of hereditary hemorrhagic telangiectasia (HHT):
• Definite clinical HHT defined as having at least 3 of the following criteria:
• Spontaneous and recurrent epistaxis.
• Multiple telangiectasias at characteristic sites: lips, oral cavity, fingers, nose.
• Visceral lesions: GI telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs.
• A first degree relative with HHT according to these criteria.
• OR a definite diagnosis of HHT based on a pathogenic genetic mutation for HHT.
• OR probable HHT based on having 2 of the above criteria with high clinical suspicion of HHT.
• Stable IV iron use and/or blood transfusions stable for 12 weeks prior to test product initiation.
• Must agree not to undergo cautery of nasal telangiectasias or to start new therapies for HHT while on study.
• Women of childbearing potential must agree to abstinence or to use an acceptable double method contraception until 4 weeks after drug termination. Pregnancy testing will be done throughout the trial.
• Men are mandated to use condoms.
• Capable of giving signed informed consent.
• Able and willing to return for outpatient visits at the protocol specified intervals.
• Able and willing to complete blood pressure monitoring at home.

You may not qualify if:

• Participant has known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib that in the opinion of the investigator contradicts their participation.
• Currently has perfused pulmonary AVMs with feeding artery diameter ≥ 3mm.
• Known significant bleeding sources other than nasal or gastrointestinal.
• Systemic use of a potent VEGF inhibitor (e.g., direct inhibitors of VEGF-receptor signaling such as sunitinib) in the 4 weeks prior to enrollment. Systemic use of bevacizumab in the 6 weeks prior to enrollment due to its longer half-life.
• Active and recent onset of clinically significant diarrhea.
• Current or recent (in the last 5 years) malignancies (except non-melanoma skin cancers)
• Participant has had major surgery (e.g. surgical ligation of an AVM) or trauma within 28 days or had minor surgical procedures (e.g. central venous access line removal) within 7 days prior to dosing, the latter representing a recent wound, fracture or ulcer
• Participant has clinically significant gastrointestinal abnormalities (other than hereditary hemorrhagic telangiectasia related vascular lesions).
• Participant during the 6 months prior to first dose of study drug has a history of cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, untreated deep vein thrombosis (DVT), myocardial infarction, or any other thrombotic event.
• Presence of intrinsic heart disease as evidenced by any of the following: Echo derived left ventricular ejection fraction \< 45%; Unstable obstructive CAD; history of MI, CABG, or PCI in the last 6 months; Infiltrative and/or restrictive cardiomyopathies; Significant pericardial disease; or clinical heart failure with more than moderate mitral valve or aortic valve disease. In the absence of clinical heart failure, EKG abnormalities, or known cardiac functional disease (e.g., MI or cardiomyopathy), a previous echo during adulthood is adequate. If there is history for coronary disease or cardiomyopathy, an echo in the past 5 years will be adequate for screening. If the patient has current clinical heart failure, a recent cardiac event in last 5 yrs, or a cardiac event since the most recent echo, an echo in the past 6 months will be necessary for screening. Clinical heart failure due to liver AVM or anemia, and not associated with the above findings (with an EF \>=45%) will be eligible for enrollment.
• Unable or unwilling to discontinue use of prohibited medications list in Section 6.5.2 for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the randomization and for the duration of the study.
• The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the start of randomization: 4 weeks, 4 half-lives or the duration of the biological effect of the investigational product (whichever is longer).
• QT corrected interval \>450 msec for men or \>460 msec for women, based on averaged QT corrected interval values of triplicate ECGs obtained over a brief recording period.
• History of familial prolonged QT.
• Any concomitant medication which is known to prolong QT.

Sponsors & Collaborators

• Cure HHT: lead

Study Sites (11)

University of California - Los Angeles

Los Angeles, California, 90095, United States

Location

University of Colorado

Denver, Colorado, 80045, United States

Location

Augusta University

Augusta, Georgia, 30912, United States

Location

John Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Texas - Southwestern

Dallas, Texas, 75390, United States

Location

University of Utah Medical Center

Salt Lake City, Utah, 84132, United States

Location

Related Publications (3)

• Clark M, Berry P, Martin S, Harris N, Sprecher D, Olitsky S, Hoag JB. Nosebleeds in hereditary hemorrhagic telangiectasia: Development of a patient-completed daily eDiary. Laryngoscope Investig Otolaryngol. 2018 Nov 14;3(6):439-445. doi: 10.1002/lio2.211. eCollection 2018 Dec.

  PMID: 30599027 BACKGROUND

• Parambil JG, Gossage JR, McCrae KR, Woodard TD, Menon KVN, Timmerman KL, Pederson DP, Sprecher DL, Al-Samkari H. Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia. Angiogenesis. 2022 Feb;25(1):87-97. doi: 10.1007/s10456-021-09807-4. Epub 2021 Jul 22.

  PMID: 34292451 BACKGROUND

• Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW, McWilliams JP, Parambil JG, Vozoris N, Donaldson J, Paul G, Berry P, Sprecher DL. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis. 2019 Feb;22(1):145-155. doi: 10.1007/s10456-018-9646-1. Epub 2018 Sep 6.

  PMID: 30191360 RESULT

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Epistaxis; Anemia

Interventions

pazopanib; Cellulose

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Glucans; Biopolymers; Polymers; Macromolecular Substances; Polysaccharides; Carbohydrates; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture

Study Officials

• James Gossage, MD

  Augusta University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Project Manager in operation will also be masked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: After at least a 6-week baseline period, participants will be assigned low dose pazopanib (150 mg) or placebo. At the termination of the 24-week Efficacy study participants will be provided the option to advance into an open label extension program including 24 weeks of treatment, followed by a 12-week non-drug follow up period. The extension would be on active drug, but otherwise blinded to the dose provided in the primary trial. This decision to continue into the extension will be based on a physician-participant discussion of any efficacy and safety concerns at week 24. A decision would be reached whether to proceed into the extension study and whether to consider a dose modification. A top dose of 150 mg will be maintained. After the extension, a 12 week follow-up time period will continue assessments to define maintenance of effect, and/ or relapse.

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: February 22, 2019
• Study Start: May 8, 2023
• Primary Completion: November 21, 2025
• Study Completion (Estimated): July 1, 2026
• Last Updated: March 19, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)